DESCRIPTION (Applicant's Description): Although malignant tumors may express protein antigens that are recognized as foreign by the immune system, tumor antigens may not elicit an immune response for several reasons. One reason is that tumors can induce a state of T cell unresponsiveness to tumor antigens. Activation of the CTLA-4 receptor on the surface of T cells is one mechanism by which tolerance can be induced. That this is a relevant mechanism for tumor evasion is demonstrated by studies showing that the in vivo blockade of CTLA-4 by anti-CTLA-4 antibodies induces the rejection of established tumors, and that rejection can result in immunity to subsequent tumor challenges. CTLA-4 was initially identified as a T cell activation gene and its amino acid sequence was found to be homologous to that of the T lymphocyte receptor CD28. CTLA-4 and CD28 were also found to bind to the same ligands. Despite the structural homology between CD28 and CTLA-4, important differences exist in their patterns of cell surface expression, their affinity for their shared ligands, and their functions in regulating T cell responses. Whereas activation of CD28 delivers signals which enhance T cell proliferation and increase cell survival, activation of CTLA-4 delivers's i g n als that inhibit T cell clonal expansion and lead to T cell unresponsiveness. The crucial role that CTLA-4 plays in regulating T cell immune responses is demonstrated by the phenotype of the CTLA-4 deficient mouse, which exhibits massive lymphoproliferation and early lethality as a result of tissue destruction from infiltrating lymphocytes. Despite the advances that have been recently made in the understanding of the functional role of CTLA-4 in immune responses, the cellular and molecular basis of CTLA-4-mediated actions are poorly understood. This proposal seeks to 1) understand the regulation of CTLA-4 cell surface expression by characterizing its intracellular trafficking within T cells; 2) determine how the interaction of the CTLA-4 cytoplasmic domain with signaling molecules regulates its function; and 3) analyze the individual roles of the extracellular and cytoplasmic domain of CTLA-4 in mediating CTLA-4 immune responses. It has been demonstrated that the CTLA-4 receptor can regulate immune responses against tumor antigens; manipulation of CTLA-4 signaling pathway(s) with the goal of enabling the immune system to reject tumors can potentially lead to clinically relevant therapies. Given the complexities of the CD28/CTLA-4 costimulatory system, a detailed understanding of the molecular basis of CTLA-4 function will be important for designing therapies which will have the highest efficacy.